Intermediates to 1,9-dihydroxyoctahydrophenanthrenes

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is hydrogen, benzyl, benzoyl, alkanoyl of 1 to 5 carbon atoms or --CO--(CH 2 ) p  --NR&#39;R&#34; wherein p is 0 or an integer from 1 to 4; each of R&#39; and R&#34; when taken individually is hydrogen or alkyl of 1 to 4 carbon atoms; R&#39; and R&#34; when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from 1 to 4 carbon atoms in the alkyl group; 
     R 2  is selected from hydrogen, alkanoyl of 1 to 6 carbon atoms and benzoyl; 
     R 3  is selected from hydrogen, methyl and ethyl; 
     R 4  is selected from hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; 
     Z is selected from: 
     (a) alkylene having from one to nine carbon atoms; 
     (b) -(alk 1 ) m  -X-(alk 2 ) n  - wherein each of (alk 1 ) and (alk 2 ) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk 1 ) plus (alk 2 ) is not greater than 9; 
     m and n are each 0 or 1; 
     X is selected from O, S, SO and SO 2  ; and 
     W is selected from hydrogen, methyl, pyridyl, piperidyl, phenyl, monochlorophenyl, monofluorophenyl and ##STR2## from hydrogen, phenyl, monochlorophenyl and monofluorophenyl; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 4, with the proviso that the sum of a and b is not greater than 5. 
     Compounds I and II are useful as analgesics. Compound III is useful as an intermediate for the preparation of Compounds I and II. Intermediates for the preparation of I, II and III are disclosed. A process for the use of Compounds I and II to produce analgesia is also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 078,474 filedSept. 24, 1979, now U.S. Pat. No. 4,270,005, which in turn is a divisionof application Ser. No. 851,503 filed Nov. 14, 1977, and now U.S. Pat.No. 4,188,495.

BACKGROUND OF THE INVENTION

This invention relates to novel 1,9-dihydroxyoctahydrophenanthrenes and1-hydroxyoctahydrophenanthren-9-ones and derivatives thereof havinganalgesic properties useful for administration to mammals includinghumans, and to intermediates useful for the preparation of saidcompounds.

Despite the current availability of a number of analgesic agents, thesearch for new and improved agents continues, thus pointing to the lackof an agent useful for the control of broad levels of pain andaccompanied by a minimum of side-effects. The most commonly used agent,aspirin, is of no practical value for the control of severe pain and isknown to exhibit various undesirable side-effects. Other, more potentanalgesic agents such as d-propoxyphene, codeine, and morphine, possessaddictive liability. The need for improved and potent analgesic agentsis, therefore, evident.

The analgesic properties of 9-nor-9β-hydroxyhexahydrocannabinol and ofother cannabinoid structures, such as Δ⁸ -tetrahydrocannabinol (Δ⁸ -THC)and its primary metabolite, 11-hydroxy-Δ⁸ -THC, have been reported byWilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11(1974), J. Med. Chem., 17, 475-476 (1974), and J. Med. Chem., 18,700-703 (1975).

U.S. Pat. Nos. 3,507,885 and 3,636,058, issued Apr. 21, 1970 and Jan.18, 1972, respectively, describe various1-hydroxy-3-alkyl-6H-dibenzo-∂b,d]pyrans having at the 9-positionsubstituents such as oxo, hydrocarbyl and hydroxy or chloro,hydrocarbylidene, and intermediates therefor.

U.S. Pat. No. 3,649,650, issued Mar. 14, 1972; discloses a series oftetrahydro-6,6,9-trialkyl-6H-dibenzo[b,d]pyran derivatives having at the1-position an w-dialkylaminoalkoxy group active as psychotherapeuticagents.

German Pat. No. 2,451,934, published May 7, 1975, describes1,9-dihyroxyhexahydrodibenzo[b,d]pyrans and certain 1-acyl derivativesthereof having at the 3-position an alkyl or alkylene group, ashypotensive, psychotropic, sedative and analgesic agents. The precursorhexahydro-9H-dibenzo[b,d]pyran-9-ones used in their preparation, andwhich are reported to have the same utility as the corresponding9-hydroxy compounds, are described in German Pat. No. 2,451,932,published May 7, 1975.

U.S. Pat. No. 3,856,821, issued Dec. 24, 1974, describes a series of3-alkoxy substituted dibenzo[b,d]pyrans having antiarthritic,antiinflammatory and central nervous system activity.

Bergel et al., J. Chem. Soc., 286-287 (1943) investigated thereplacement of the pentyl group at the 3-position of7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olby alkoxy (butoxy, pentyloxy, hexyloxy and octyloxy) and found that itled to biological inactivity. The hexyloxy derivative was reported toexhibit feeble hashish activity at 10 to 20 mg./kg. The remaining ethersshowed no activity in doses up to 20 mg./kg.

In a more recent study, Loev et al., J. Med. Chem., 16, 1200-1206 (1973)report a comparison of7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olsin which the 3-substituent is --OCH(CH₃)C₅ H₁₁ ; or --CH(CH₃)C₅ H₁₁. Theether side chain containing compound was 50% less active in centralnervous system activity than the corresponding compound in which thealkyl side chain is directly attached to the aromatic ring, rather thanthrough an intervening oxygen atom; and 5 times as active as thecompound in which oxygen is replaced by methylene.

Co-pending U.S. Pat. application Ser. No. 819,471 filed July 27, 1977discloses a series of 1,9-hydroxy-hexahydrodibenzo[b,d]pyrans andintermediates therefor having analgesic and other therapeuticactivities. Co-pending U.S. Pat. application Ser. No. 777,928 filed Mar.15, 1977 discloses a series of 1,9-dihydroxyoctahydrobenzo[c]quinolinesand intermediates therefor also having analgesic and other therapeuticactivities.

Mechoulam and Edery in "Marijuana", edited by Mechoulam, Academic Press,New York, 1973, page 127, observe that major structural changes in thetetrahydrocannabinol molecule seem to result in steep reductions inactivity.

Paton, in Annual Review of Pharmacology, 15, 192 (1975) presentsgeneralizations on structure-action relationships among cannabinoids.The presence of the gem dimethyl group in the pyran ring is critical forcannabinoid activity and substitution of N for O in the pyran ringremoves activity. Paton also reports that substitution of a --CH₂ --group for oxygen in the pyran ring to produce phenanthrenes has not beenexamined.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of the formulae##STR3## wherein R₁ is hydrogen, benzyl, benzoyl, alkanoyl of 1 to 5carbon atoms or --CO--(CH₂)_(p) NR'R" wherein p is 0 or an integer from1 to 4; each of R' and R" when taken individually is hydrogen or alkylof 1 to 4 carbon atoms; R' and R" when taken together with the nitrogento which they are attached form a 5- or 6-membered heterocyclic ringselected from piperidino, pyrrolo, pyrrididino, morpholino andN-alkylpiperazino having from 1 to 4 carbon atoms in the alkyl group;

R₂ is selected from hydrogen, alkanoyl of 1 to 6 carbon atoms andbenzoyl;

R₃ is selected from hydrogen, methyl and ethyl;

R₄ is selected from hydrogen, alkyl of 1 to 6 carbon atoms and benzyl;

Z is selected from:

(a) alkylene having from one to nine carbon atoms;

(b) --(alk₁)_(m) --X--(alk₂)_(n) -- wherein each of (alk₁) and (alk₂) isalkylene having from 1 to 9 carbon atoms, with the proviso that thesummation of carbon atoms in (alk₁) plus (alk₂) is not greater than 9;

m and n are each 0 or 1;

X is selected from O, S, SO and SO₂ ; and

W is selected from hydrogen, methyl, pyridyl, piperidyl, phenyl,monochlorophenyl, monofluorophenyl and ##STR4## from hydrogen, phenyl,monochlorophenyl and monofluorophenyl; a is an integer from 1 to 5 and bis 0 or an integer from 1 to 4, with the proviso that the sum of a and bis not greater than 5.

Compounds of formulae I and II are effective as analgesic agents and arenon-narcotic and free of addiction liability. These compounds also haveutility as antihypertensives, immunosuppressants, tranquilizers,diuretics and as anti-anxiety drugs and as agents for the treatment ofglaucoma. Compounds of formula II are useful as intermediates for theformation of analgesic agents of formula I. Compounds of formula III areuseful as intermediates for the formation of compounds of the formulae Iand II.

Of particular interest as analgesics are the compounds of formula I asdefined above. In such compounds R₁ and R₂ are preferably hydrogen oralkanoyl and R₃ and R₄ are preferably hydrogen, methyl, or ethyl. Onepreferred group for Z is alkylene of 4 to 9 carbon atoms, mostpreferably --CH(CH₃)--(CH₂)₃ --. A further particularly preferredalkylene group for Z is 1,2-dimethylhexylene, especially where W ismethyl. Another preferred group for Z is (alk₁)_(m) --X--(alk₂)_(n),especially (alk₁)_(m) --O--(alk₂)_(n). Most preferably Z is --O--(alk₂)where (alk₂) has from 4 to 9 carbon atoms, especially--O--CH(CH₃)--(CH₂)₃ --. Preferred groups for W are hydrogen, methyl andphenyl, with phenyl being especially preferred. The compound of formulaI where R₁ and R₂ are each hydrogen, R₃ and R₄ are each methyl, Z is--O--CH(CH₃)--(CH₂)₃ -- and W is phenyl is a compound of particularinterest for its utility as an analgesic agent. A further preferredcompound of formula I having analgesic activity is that where R₁, R₂, R₃and R.sub. 4 are each hydrogen, Z is --O--CH(CH₃)-- (CH₂)₃ -- and W isphenyl.

Compounds of formula II are intermediates for the preparation of thecorresponding compounds of formula I and are also useful as analgesicagents. Preferred substituents R₁, R₂, R₃, R₄, Z and W are thosedescribed above for the corresponding compounds of formula I.

Compounds of formula III are useful as intermediates for the preparationof the corresponding compounds of formulae I and II. Preferredintermediates are those useful for the preparation of the preferredcompounds of formulae I and II described above herein. Thus, preferredvalues of the substituents R₁, R₂, R₃, R₄, Z and W are those describedabove for the preferred compounds of formula I.

Also disclosed is a process for producing analgesia in a mammal whichcomprises administering to the mammal an analgesia producing quantity ofa compound of formulae I or II. The analgesia-producing compound is mostpreferably of formula I. Compounds of formula II are also preferredcompounds for use in the present process. Preferred compounds of eitherformula I or II for use in the above process to produce analgesia in themammal are those having the preferred groups of R₁, R₂, R₃, R₄, Z and Was described above herein.

Further useful intermediates for the preparation of compounds offormulae I, II and III are also disclosed. Such useful intermediatesinclude those of the formulae ##STR5##

wherein R₁ ' is hydrogen, alkanoyl of 1 to 6 carbon atoms and benzoyl;R₃, R₄, Z and W are as defined above;

R₅ is selected from hydrogen, alkyl of 1 to 6 carbon atoms and benzyl,with the proviso that when Z is --O--(alk₂), R₅ is benzyl; and R₆ and R₇are each selected from --CN and --COOR₀, wherein R₀ is alkyl of 1 to 3carbon atoms.

Preferred intermediates of these formulae are those useful for preparingthe preferred compounds of formulae I, II and III as previouslydescribed.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula III are readily prepared from the corresponding3,3-(R₃ R₄)-6-(Z-W)-8-(OR₁ ')-1-tetralones of formula IV, the reactionsequence being shown in reaction scheme 1. ##STR6##

The 3,3-(R₃ R₄)-6-(Z-W)-(OR'₁)-1-tetralone is first reacted with ethylformate in the presence of an alkali metal hydride such as sodiumhydride. The resulting 2-hydroxymethylene-3,3-R₃ R₄-6-(Z-W)-8-(OR'₁)-1-tetralone is reacted with methyl vinyl ketone in thepresence of a base, such as an alkali metal hydroxide or alkoxide or atertiary organic amine, such as triethylamine, to effect Michaeladdition. The formed 2-(3'-oxobutyl)-2-formyl-3,3-(R₃R₄)-6-(Z-W)-8-(OR'₁)-1-tetralone is then treated with a base, forexample an alkali metal hydroxide or alkoxide to complete aldolcyclization to form the desired compound of formula III.

Compounds of formula III are converted by Birch reduction to thecorresponding compounds of formula II using an alkali metal such aslithium, sodium or potassium and ammonia. The reduction may be conductedat a temperature of about -35° C. to about -80° C. Reduction ofcompounds of formula II occurs with an excess of the alkali metal or canbe carried out with a metal hydride to afford the compounds of formula Iwhere R₂ is hydrogen. Suitable metal hydrides include lithium aluminumhydride, lithium borohydride and sodium borohydride. Sodium borohydrideis a preferred reducing agent for this reaction since it reacts slowlyenough with hydroxylic solvents to allow their use as solvents. Suitablesolvents include methanol, ethanol and water. Temperatures between about0° and 30° C. may be used, but preferably temperatures below 0° C. anddown to about -70° C. are employed. At higher temperatures reaction ofthe sodium borohydride with the hydroxylic solvent may ocur. If desired,higher reaction temperatures may be employed by use of isopropylalcohol, or the dimethyl ether of diethylene glycol as solvent. Whenlithium borohydride or lithium aluminum hydride are used as the reducingagent, anhydrous conditions and non-hydroxylic solvents are employed attemperatures between about -70° C. and about 0° C. Suitable solventsinclude 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether and thedimethyl ether of diethylene glycol.

Esters of compounds of formulae II and III wherein R₁ is alkanoyl, andesters of compounds of formula I wherein each of R₁ and R₂ is alkanoyl,are readily prepared by reacting the corresponding compounds wherein R₁and R₂ are hydrogen with the appropriate alkanoic acid in the presenceof a condensing agent such as dicyclohexylcarbodiimide. Alternatively,they may be prepared by reaction with the appropriate alkanoic acidchloride or anhydride in the presence of a base such as pyridine.Similarly, compounds of formulae I, II and III where R₁ is--CO--(CH₂)_(p) --NR'R" are prepared by analagous reactions, for exampleby condensation with an acid of the formula HOOC--(CH₂)_(p) --NR'R".Compounds of formula I in which only the 9-hydroxy group is acylated areobtained by mild hydrolysis of the corresponding 1,9-diacyl derivative,advantage being taken of the greater ease of hydrolysis of the phenolicacyl group. Compounds of formula I in which only the 1-hydroxy group isesterified are obtained by borohydride reduction of the corresondingformula II ketone esterified at the 1-position. The thus producedformula I compound having 1-acyl-9-hydroxy substitution or1-hydroxy-9-acyl substitution can then be acylated further with adifferent acylating agent to produce a diesterified compound of formulaI in which the ester group at the 1- and the 9-positions are different.

The 3,3-(R₃ R₄)-6-(Z-W)-8-(OR'₁)-1-tetralone of formula IV startingmaterial for the above reaction sequence may be synthesized from anappropriate 5-(Z-W)-3-(OY₁)-benzyl halide, where Y₁ is alkyl of 1 to 4carbon atoms, preferably methyl, benzyl or substituted benzyl. Thereaction sequence is shown in reaction scheme 2. The (OY₁)-substituentserves as a protected hydroxyl group, the protecting alkyl or aryl groupbeing removed later in the synthesis. When Z is alkylene, Y₁ isdesirably methyl or benzyl. When Z is (alk₁)_(m) -X-(alk₂)_(n), Y₁ ispreferably benzyl or substituted benzyl, since it can be subsequentlyremoved to form a hydroxyl group without detriment to the Z group. AGrignard reagent is first prepared by reacting the substituted benzylhalide with powdered magnesium in a suitable solvent such astetrahydrofuran. This is then reacted with an appropriate alkylidenemalonate derivative, as shown in scheme 2. The alkylidene malonatederivative may be formed by the condensation of a suitable aldehyde ofthe formula R₃ CHO or ketone of the formula R₃ R₄ CO, with an alkylcyanoacetate, dialkyl malonate or dicyano malonate. Preferably, thealkyl group of the malonate ester derivative is of 1 to 3 carbon atoms.The reaction is effected in a suitable solvent such as tetrahydrofuranat a temperature below about 10° C. ##STR7## The product is hydrolyzedby treatment with an alkali metal hydroxide in alcohol solution,preferably sodium or potassium hydroxide in methanol or ethanol,followed by acidification. Cyclization to form the 3,3-(R₃R₄)-6-(Z-W)-8-hydroxy-1-tetralone is conveniently effected by refluxingwith aqueous hydrogen bromide in glacial acetic acid, whendecarboxylation, cyclization and conversion of alkoxy or aryloxy tohydroxy by removal of the Y₁ group is effected in the one step. Thesereactions may be effected stepwise, if desired. The 3,3-(R₃R₄)-6-(Z-W)-8-hydroxy-1-tetralone may be used as a starting material forthe synthesis of compounds of formulae I, II and III. Preferably,however, the B 8-hydroxy group is protected by reaction with a benzylhalide, methyl iodide or dimethyl sulfate. A preferred protecting groupwhen Z-W is joined to the tetralone ring by oxygen or sulfur is benzyl.

In an alternative method, the Z-W substituent may be introduced duringthe reaction sequence, as also shown in reaction scheme 2. This is aparticularly useful and preferred method for preparation of compoundshaving an oxygen or sulfur atom linking the Z group to the tetralonering. Suitable starting materials are 3,5-(OY₁)-benzyl halides and thecorresponding 3,5-(SY₁)-benzyl halides. Y₁ is as previously defined andis preferably methyl or benzyl. The substituted benzyl halide isconverted to a Grignard reagent, reacted with an appropriate alkylidenemalonate derivative and cyclized, as described previously. The Z-W groupis then introduced by reaction with one equivalent of an appropriate Z-Wmethane sulfonate, which reacts with the 6-hydroxy or 6-thiol group ofthe tetralone. The reaction is conveniently effected in the presence ofa base, preferably an alkali metal hydride such as sodium or potassiumhydride, or an alkali metal carbonate such as potassium or sodiumcarbonate, in a suitable organic solvent such as dimethyl formamide oracetone. The reaction is preferably conducted in an inert atmosphere attemperatures between about 60° C. and 100° C. The Z-W methane sulfonateis a preferred reagent for introduction of the Z-W group in the6-position of the tetralone. However, any reagent that will react withthe --OH or --SH group and allow introduction of the Z-W group at the6-position of the cyclized intermediate may be used. Suitablealternative reagents include the corresponding Z-W halides, preferablythe bromide or iodide.

Compounds where the Z group contains --SO-- or SO₂ groups areconveniently prepared by oxidation of compounds containing sulfur in theappropriate position of the 6-(Z-W)-substituent of the tetralone, whichare prepared by the methods described above. The oxidation may beeffected at any subsequent stage of the synthesis but most convenientlycompounds of formula II are oxidized. Compounds of formula III may alsobe oxidized to convert S to SO or SO₂ in the Z group. The oxidation toSO may be carried out by using one equivalent of a period such asm-chloroperbenzoic acid, perbenzoic acid and other such acids, which maybe prepared in situ from a mixture of the corresponding carboxylic acidand hydrogen peroxide. The reaction is conducted at a temperaturebetween about 0° C. and 25° C., preferably about 0° C. and 10° C. Usingtwo equivalents of a peracid the corresponding compound where Z containsan SO₂ group are obtained.

5-(Z-W)-3-(OY₁)-substituted benzyl halides useful for the preparation ofthe tetralone starting materials are known in the art or may besynthesized by the following procedures. 3-methoxy isophthalaldehydicacid methyl ester is prepared from 3-methoxy isophthalic acid dimethylester by reduction with diisobutyl aluminum hydride. The formyl groupmay then be reacted with Wittig reagents to introduce the Z-W group. Bychoice of appropriate reagents straight or branched alkylene groups canbe introduced. The Wittig reaction is effected by use of an alkylidenetriphenylphosphorane. The Z-W substituent is formed by catalyticreduction of the unsaturated side chain using platinum or palladium oncarbon as a catalyst. Reduction of the ester function with excesslithium aluminum hydride in ether at reflux temperature andacidification yields the corresponding 1-(Z-W)-3-methoxy-benzyl alcohol.The latter is converted to the corresponding benzyl halide by reactionwith a thionyl halide, preferably thionyl chloride, at refluxtemperature. The formed substituted benzyl halide may be purified ifdesired by recrystallization, column chromatography or vacuumdistillation. For compounds with an α-branch in the Z-W side chain, the3-methoxy isophthalaldehydic acid dimethyl ester is hydrolyzed by diluteacid or base to yield the half ester acid. The carboxyl group is reactedwith thionyl chloride to form the acid chloride, which is then reactedwith diethyl malonate as the ethoxy magnesium salt. Hydrolysis by diluteacid and decarboxylation produces methyl 3-methoxy-5-acetyl benzoate.The carbonyl group of the acetyl substituent is then converted to theZ-W group by the Wittig reaction and the carbomethoxy group subsequentlyreduced to form the benzyl halide by the sequences described above.

Substituted benzyl halides of the type ##STR8## where Q' is hydrogen ormethyl and Q is alkyl, alkyloxyalkyl and alkylthioalkyl may be preparedby Friedel-Crafts alkylation of m-cresol. Meta substitution is effectedunder forcing conditions using excess aluminum chloride catalyst andreflux temperatures, see "Anhydrous Aluminum Chloride in OrganicChemistry", Reinhold Publishing Corporation, New York, 1941, page 181.The phenolic group is conveniently protected at this time inanticipation of the formation of a Grignard reagent later in thesynthesis. This can be done by reaction with, for example, methyliodide, dimethyl sulfate or benzyl chloride. Subsequent brominationusing N-bromosuccinimide yields the desired substituted benzyl bromide.

A further method of preparing the substituted benzyl halides useful forpreparation of the tetralone starting materials is from1-acetyl-3-nitro-5-carboalkoxy-benzene, where alkoxy is of 1 to 4 carbonatoms. See Chem. Abs. 57 13663a, Zh. Obshch Khim 32, 293 (1962). Thecarbonyl group of the acetyl substituent is reacted with Wittig reagentsto introduce the Z-W side chain as previously described, followed bycatalytic reduction over platinum or palladium on carbon. The reductionis effective to reduce both the double bond in the Z group and toconvert the nitro group to amino. Diazotisation of the amino group withhydrochloric acid and sodium nitrite in water yields the correspondingphenol which is then protected by reaction with methyl iodide, dimethylsulfate or benzyl chloride. The ester function is then reduced withlithium aluminum hydride to yield the benzyl alcohol. The correspondingbenzyl halide is prepared by reaction of the benzyl alcohol with thionylchloride or phosphorous pentachloride.

3-methoxy isophthalaldehydic acid methyl ester, 3-methoxy-5-acetylbenzoate and analagous compounds may also be used in an alternativesynthesis of the substituted tetralone starting materials of formula IV,which is especially useful when W is a nitrogen-containing heterocyclicgroup. It is also a preferred method for preparing compounds where Z is-(alk₁)_(m) -S-(alk₂)_(n) - and m is one. In this method, the carbonylfunction of the formyl or acetyl substituent is first protected byforming an acetal or ketal. This may be effected by reaction with asuitable glycol such as, but not limited to, ethylene glycol in thepresence of a catalytic amount of a strong acid such asp-toluenesulfonic acid or sulfuric acid. The protected compound is thenconverted to a substituted benzyl halide, via reduction to thesubstituted benzyl alcohol and subsequent reaction with a thionylhalide. The protected benzyl halide so formed is converted to a Grignardreagent, reacted with an appropriate alkylidene malonate derivative,followed by hydrolysis and cyclization, as described in detail for thesereaction steps previously, to form a 3,3-(R₃ R₄)-8-hydroxy-1-tetralonehaving at the 6-position the acetal- or ketal-protected formyl or acetylgroup, depending on the starting material. The carbonyl function of the6-substituent is regenerated by hydrolysis of the acetal or ketal toremove the protecting group. The Z-W substituent is then introduced bythe reaction of the carbonyl group with a Wittig reagent as previouslydescribed. The carbonyl group at the 1-position of the tetralone ringreacts relatively slowly with Wittig reagents, thus allowingpreferential reaction at the 6-substituent. However, if desired,increased yields of the (Z-W)-substituted tetralone can be obtained byfirst protecting the carbonyl group at the 1-position, for example byformation of a ketal.

It will be understood that compounds of formulae I, II and III containasymmetric centers at the 6a and/or 10a-positions. There may beadditional asymmetric centers in the 3-position substituent Z-W, the6-position and the 9-position. Diastereomers with the 9β-configurationare generally favored over the 9β-isomers because of greater(quantitatively) biological activity. For the same reason, thetrans(6a,10a)diastereomers of compounds of formula I are generallyfavored over the cis (6a,10a)diastereomers. Among the enantiomers of agiven compound, one will generally be favored over the other and theracemate because of its greater activity. The enantiomer favored isdetermined by the procedures described below herein. For convenience,the formulae shown in the specification and claims hereof depict theracemic compounds. However, these formulae are considered to be genericto and embracive of the racemic modifications of the compounds of thisinvention, the diastereomeric mixtures, the pure enantiomers anddiastereomers thereof. The utility of the racemic mixtures, thediastereomeric mixtures as well as of the pure enantiomers anddiastereomers is determined by the biological evaluations describedbelow.

The compounds of formulae I and II of the present invention are activeanalgesic agents via oral and parenteral administration and areconveniently administered in composition form. Such compositions includea pharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. For example, theymay be administered in the form of tablets, pills, powders or granulescontaining such excipients as starch, milk sugar, certain types of clay,etc. They may be administered in capsules, and in mixtures with the sameor equivalent excipients. They may also be administered in the form oforal suspensions, solutions, emulsions, syrups and elixirs which maycontain flavoring or coloring agents. For oral administration of thetherapeutic agents of this invention, tablets or capsules containingfrom about 0.01 to about 100 mg are suitable for most applications. Thephysician will determine the dosage which will be most suitable for anindividual patient and it will vary with the age, weight and response ofa particular patient and the route of administration. Generally,however, the initial analgesic dosage in adults may range from 0.01 to500 mg per day in single or divided doses. In many instances, it is notnecessary to exceed 100 mg daily. The favored oral dosage range is fromabout 0.01 to about 300 mg per day; the preferred range is from about0.10 to about 50 mg per day. The favored parenteral dose is from about0.01 to about 100 mg per day; the preferred range is from about 0.01 toabout 20 mg per day.

The analgesic properties of the compounds of this invention aredetermined by tests using nociceptive stimuli.

TESTS USING THERMAL NOCICEPTIVE STIMULI

(a) Mouse Hot Plate Analgesic Testing

The method used is modified after Woolfe and MacDonald, J. Pharmacol.Exp. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied tothe feet of mice on a 1/8" thick aluminum plate. A 250 watt reflectorinfrared heat lamp is placed under the bottom of the aluminum plate. Athermal regulator, connected to thermistors on the plate surface,programs the heat lamp to maintain a constant temperature of 57° C. Eachmouse is dropped into a glass cylinder (61/2 diameter) resting on thehot plate, and timing is begun when the animal's feet touch the plate.The mouse is observed at 0.5 and 2 hours after treatment with the testcompound for the first "flicking" movements of one or both hind feet, oruntil 10 seconds elapse without such movements. Morphine has an MPE₅₀=4-5.6 mg./kg. (s.c.).

(b) Mouse Tail Flick Analgesic Testing

Tail flick testing in mice is modified after D'Amour and Smith, J.Pharmacol. Exp. Ther., 72, 74-79 (1941), using controlled high intensityheat applied to the tail. Each mouse is placed in a snug-fitting metalcylinder, with the tail protruding through one end. This cylinder isarranged so that the tail lies flat over a concealed heat lamp. At theonset of testing, an aluminum flag over the lamp is drawn back, allowingthe light beam to pass through the slit and focus onto the end of thetail. A timer is simultaneously activated. The latency of a sudden flickof the tail is ascertained. Untreated mice usually react within 3-4seconds after exposure to the lamp. The end point for protection is 10seconds. Each mouse is tested at 0.5 and 2 hours after treatment withmorphine and the test compound. Morphine has an MPE₅₀ of 3.2-5.6 mg./kg.(s.c.).

(c) Tail Immersion Procedure

The method is a modification of the receptacle procedure developed byBenbasset, et al., Arch. Int. Pharmacodyn., 122, 434 (1959). Male albinomice (19-21 g.) of the Charles River CD-1 strain are weighed and markedfor identification. Five animals are normally used in each drugtreatment group with each animal serving as its own control. For generalscreening purposes, new test agents are first administered at a dose of56 mg./kg. intraperitonally or subcutaneously, delivered in a volume of10 ml./kg. Preceeding drug treatment and at 0.5 and 2 hours post drug,each animal is placed in the cylinder. Each cylinder is provided withholes to allow for adequate ventilation and is closed by a round nylonplug through which the animal's tail protrudes. The cylinder is held inan upright position and the tail is completely immersed in the constanttemperature waterbath (56° C.). The endpoint for each trial is anenergetic jerk or twitch of the tail coupled with a motor response. Insome cases, the endpoint may be less vigorous post drug. To preventundue tissue damage, the trial is terminated and the tail removed fromthe Waterbath within 10 seconds. The response latency is recorded inseconds to the nearest 0.5 second. A vehicle control and a standard ofknown potency are tested concurrently with screening candidates. If theactivity of a test agent has not returned to baseline values at the2-hour testing point, response latencies are determined at 4 and 6hours. A final measurement is made at 24 hours if activity is stillobserved at the end of the test day.

TEST USING CHEMICAL NOCICEPTIVE STIMULI Suppression ofPhenylbenzoquinone Irritant-Induced Writhing

Groups of Carworth Farms CF-1 mice are pretreated subcutaneously ororally with saline, morphine, codeine or the test compound. Twentyminutes (if treated subcutaneously) or fifty minutes (if treated orally)later, each group is treated with intraperitoneal injection ofphenylbenzoquinone, an irritant known to produce abdominal contractions.The mice are observed for 5 minutes for the presence or absence orwrithing starting 5 minutes after the injection of the irritant. MPE₅₀'s of the drug pretreatments in blocking writhing are ascertained.

TESTS USING PRESSURE NOCICEPTIVE STIMULI Effect on the Haffner TailPinch Procedure

A modification of the procedure of Haffner, Experimentelle PrufungSchmerzstillender. Mittel Deutch Med. Wschr., 55, 731-732 (1929) is usedto ascertain the effects of the test compound on aggressive attackingresponses elicited by a stimulus pinching the tail. Male albino rats(50-60 g.) of the Charles River (Sprague-Dawley) CD strain are used.Prior to drug treatment, and again at 0.5, 1, 2 and 3 hours aftertreatment, a Johns Hopkins 2.5-inch "bulldog" clamp is clamped onto theroot of the rat's tail. The endpoint at each trial is clear attackingand biting behavior directed toward the offending stimulus, with thelatency for attack recorded in seconds. The clamp is removed in 30seconds if attacking has not yet occurred, and the latency of responseis recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).

TESTS USING ELECTRICAL NOCICEPTIVE STIMULI The "Flinch-Jump" Test

A modification of the flinch-jump procedure of Tenen,Psychopharmacologia, 12, 278-285 (1968) is used for determining painthresholds. Male albino rats (175-200 g.) of the Charles River(Sprague-Dawley) CD strain are used. Prior to receiving the drug, thefeet of each rat are dipped into a 20% glycerol/saline solution. Theanimals are then placed in a chamber and presented with a series of1-second shocks to the feet which are delivered in increasing intensityat 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78,1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal'sbehavior is rated for the presence of (a) flinch, (b) squeak and (c)jump or rapid forward movement at shock onset. Single upward series ofshock intensities are presented to each rat just prior to, and at 0.5,2, 4 and 24 hours subsequent to drug treatment.

Results of the above tests are recorded as percent maximum possibleeffect (% MPE). The % MPE of each group is statistically compared to the% MPE of the standard and the predrug control values. The % MPE iscalculated as follows: ##EQU1##

For example, the analgesic properties of compounds of formulae I and IIhave been determined according to the above-described procedures withthe results shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                    MPE.sub.50 (mg./kg. s.c.)                                                                                  Time                                 Compound      PBQ    TF      HP     RTC  (hr)                                 ______________________________________                                        Trans-6a,10a-1-hydroxy-                                                                     0.78   --      --     --    0.33                                3-(5'-phenyl-2'-pentyl-                                                                            3.3     29% @10                                                                              --   0.5                                  oxy)-6,6-dimethyl-5,6,6a,                                                                          1.3     2.5    1.1  2.0                                  7,8,9,10,10a,-octahydro-                                                                           1.5     1.9    0.74 4.0                                  phenanthren-9-β-ol                                                                            --      --     0.66 6.0                                                       3.5     6.4    0.88 8.0                                                       2.2     27% @10                                                                              --   24.0                                 Trans-6a,10a-1-hydroxy-                                                       3-(5'-phenyl-2'-pentyl-                                                                     10     --      --     --    0.33                                oxy)-6,6-dimethyl-5,6,6a,                                                     7,8,9,10,10a-octahydro-                                                                            *       *      --   0.5                                  phenanthren-9-one                                                             1-hydroxy-3-(5'-phenyl-                                                                     0.32-  --      --     --                                                      0.56                        0.33                                2'-pentyloxy)-5,6,6a,7,                                                                            1.6     --     --   0.5                                  8,9,10,10a-octahydro-                                                                              2.7     10     --   1.0                                  phenanthren-9-ol     11.4    --     --   2.0                                  1-hydroxy-3-(5'-phenyl-                                                                     17.8-  --      --     --    0.33                                2'-pentyloxy)-5,6,6a,7,                                                                     56                                                              8,9,10,10a-octahydro-                                                         phenanthren-9-one                                                             Morphine      0.8    --      --     --    0.33                                                     3.2-5.6   4-5.6     0.5                                  ______________________________________                                         PBQ =  pbiphenylquinone writhing test                                         TF = Tail Flick test                                                          HP = Hot Plate test                                                           RTC = Rat Tail Clamp test                                                     Time = Time interval between administration of the drug and measurement o     the analgesic affect in the above analgesic test procedures.                  * = Inactive at 10                                                       

Antihypertensive utility is determined by their ability to lower theblood pressure of conscious hypertensive rats and dogs a statisticallysignificant degree when administered to said hosts at dosages equivalentto those described previously for use as analgesics.

Tranquilizer activity is demonstrated by oral administration to rats atdoses of from about 0.01 to 50 mg./kg. with subsequent decreases inspontaneous motor activity. The daily dosage range in mammals is fromabout 0.01 to about 100 mg.

The use of compounds of the present invention for the treatment ofglaucoma is believed to be due to their ability to reduce intraocularpressure. Their effects on intraocular pressure are determined by testson dogs. The test drug is instilled into the eye of a dog in the form ofa solution or is administered systemically at various periods of timeafter which the eye is anesthetized by instillation of tetracainehydrochloride, 1/2%, 2 drops. A few minutes after this local anesthesia,intraocular pressure readings are taken with a Schiotz mechanicaltonometer and, after fluorescein dye is administered, with a Holberghand application tonometer. The test drug is conveniently used in asolution such as the following: test drug (1 mg.), ethanol (0.05 ml.),Tween 80 (polyoxyalkylene derivative of sorbitan mono-oleate, availablefrom Atlas Powder Co., Wilmington, Delaware 19899) (50 mg.) and saline(to make 1 ml.), or in a more concentrated solution wherein theingredients are present in proportions of 10 mg., 0.10 ml., 100 mg. and1 ml., respectively. For human use, concentrations of drug from 0.01mg./kg. to 10 mg./kg. are useful.

Activity as diuretic agents is determined by the procedure of Lipschitzet al., J. Pharmacol., 79, 97 (1943) which utilizes rats as the testanimals. The dosage range for this use is the same as that noted abovewith respect to the use of the herein described compounds as analgesicagents.

Gastric antisecretory activity is determined by tests on overnightfasted, conscious Heidenhain pouch dogs using pentagastrin, histamine orfood to stimulate acid output. Pentagastrin or histamine is administeredas a continuous infusion into a superficial leg vein at doses earlierdetermined to stimulate near maximal acid output from the gastric pouch.Food stimulus consists of one-half can of Ken-L-Ration (approx. 220 g.)per dog; dogs weighing 9-12.5 kg. are used. Gastric juice is collectedat 30 minute intervals following the start of a histamine orpentagastrin infusion or the ingestion of a standard food meal. A totalof ten collections are made for each dog during an experiment. Drug isadministered orally at levels of from 0.01 to 50 mg./kg. after the thirdgastric juice collection. All sample volumes are recorded and acidconcentration is determined by titrating sample aliquots (1.0 ml.) to pH7.4 with 0.1 N NaOH using a pH meter (Radiometer) and autoburette. Thedrug is given orally after placing it in gelatin capsules.

Immunosuppressant activity is evaluated by means of a mixed lymphocyteculture assay procedure. This assay measures the effects of the testcompounds on antigen-stimulated lymphocyte proliferation. Spleenlymphoid cells from BALB/C and C57BL/6 mice, 8×10⁶ cells from eachstrain, are suspended in 2.0 ml. of a serum-free medium containing thetest compound and incubated at 37° C. in a 10% carbon dioxideatmosphere. The culture conditions and technique are described by R. W.Dutton in J. Exp. Med., 122, 759 (1965) and the cellular medium isdescribed by W. T. Weber in J. Retic. Soc., 8, 37 (1970). Half of themedium, 1 ml., is replaced with fresh medium every 24 hours. ³ H-TdRincorporation (24 hour pulse) into desoxyribonucleic acid is thendetermined by trichloroacetic acid precipitation of desoxyribonucleicacid and assessment of radioactivity in a liquid scintillation counter.The percent inhibition is determined by comparing each testcompound-treated mixed culture with the control mixed culture.

The present invention is further illustrated by the following examples.It should be noted, however, that the invention is not limited to thespecific details of these examples.

EXAMPLE 12-Hydroxymethylene-3,3-dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone

A solution of 258 mg (0.58 mmoles) of3,3-dimethyl-6(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone in 2.5 mlof ethyl formate was added dropwise to 144 mg (3.0 mmoles) of 50% sodiumhydride (washed with pentane) and after dilution with 10 ml of ether wasstirred overnight at room temperature. The reaction mixture was pouredinto an ice cold mixture of 1 N hydrochloric acid and ether, the etherlayer was separated, and the aqueous was extracted once with ether. Thecombined ether layers were washed with water (2×), dried (brine,magnesium sulfate), and concentrated to give 257 mg (94%) of the desiredcompound as a yellow oil.

NMR: CDCl₃ (TMS); δ: 16.0 (D, 1H, J=8Hz, hydroxylic), 7.8 (D, 1H, J=8Hz,vinyl), 7.7-7.0 (M, 10H, phenyls), 6.4-6.2 (M, 2H, aromatic), 6.2 (S,2H, benzyloxy methylene), 4.7-4.1 (M, 1H, methane), 2.9-2.4 (M, 5H,benzylmethylene), 2.0-1.5 (M, 4H, ethylene), 1.3 (D, 3H, α-methyl), 1.2(S, 6H, gem-dimethyl).

EXAMPLE 22-(3'-oxobutyl)-2-formyl-3,3-dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone

A 257 mg portion of (0.55 mmoles) of2-hydroxymethylene-3,3-dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralonesuspended in 1 ml methanol was stirred with 0.08 ml of methyl vinylketone and 0.018 ml triethylamine for 2.5 days at room temperature. Thereaction mixture was diluted with ether, washed four times with anaqueous solution of 10% sodium carbonate, and after drying (brine,magnesium sulfate), the ether layer was concentrated to give a yellowoil which was chromatographed on 15 g of silica gel eluted withether/pentane (1:1). Combination and concentration of the appropriatefractions gave 99 mg (33.5%) of the desired compound as an oil.

EXAMPLE 31-Benzyloxy-3-(5'-phenyl-2'-pentyloxy)-6,6-dimethyl-6a,7,8,9-tetrahydrophenanthren-9-one

A 99 mg (0.183 mmoles) portion of2-(3'-oxobutyl)-2-formyl-3,3-dimethyl-6-(5'-phenyl-2-pentyloxy)-8-benzyloxy-1-tetralonedissolved in 1 ml of methanol was reacted with 0.18 ml of 2N potassiumhydroxide in methanol at 0° C. After stirring 1.5 hours, the reactionmixture was diluted with 1.36 ml of methanol and treated with anadditional 2.36 ml of 2 N potassium hydroxide in methanol and heated toreflux, under nitrogen atmosphere, overnight. The reaction mixture wasneutralized at room temperature with acetic acid, concentrated to asolid residue, and taken up in a mixture of ether-water. The ether layerwas separated and the aqueous layer was extracted twice more with ether.The combined ether extracts were washed twice with saturated sodiumbicarbonate, dried (brine, magnesium sulfate), and concentrated to anoil, which was chromatographed on 5 g silica gel eluted withether/pentane (1:1). Combination and concentration of the appropriatefractions gave 51 mg (56%) of the desired tri-cyclic compound as an oil.

NMR: CDCl₃ ; δ : 7.6-6,9 (M, 11H, phenyls and vinylic), 6.3 and 6.2 (twoD, 2H, J=2Hz, aromatic), 5.1 (S, 2H, benzyloxy methylene) 1.1 and 0.8(2S, 6H, gem-dimethyl).

EXAMPLE 4Trans-6a,10a-1-hydroxy-3-(5'-phenyl-2'-pentyloxy)-6,6-dimethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthren-9-one

55 ml of ammonia was liquified in a flame-dried apparatus placed into adry ice/acetone bath. A piece of lithium wire was then dissolved in theammonia to produce a deep blue colored solution and 276 mg (0.55 mmoles)of1-benzyloxy-3-(5'-phenyl-2'-pentyloxy)-6,6-dimethyl-6a,7,8,9-tetrahydrophenanthren-9-onedissolved in 7 ml of dry tetrahydrofuran was slowly added after whichthe mixture was stirred for 10 minutes at -80° before solid ammoniumchloride was carefully added until all the blue color disappeared. Theliquid ammonia was evaporated and 75 ml of water was added to theresidue which was then extracted with ether (4×50 ml). The etherextracts were combined, dried (brine, magnesium sulfate), filtered andconcentrated to give a red oil which was chromatographed on 90 g ofsilica gel eluted with 25% ether/hexane. Similar fractions were combinedand concentrated to give 76 mg (34%) of the desired trans-isomer as anoil.

NMR: 100MHz; CDCl₃ δ: 7.5-7.0 (m, 6H, phenyl and phenolic); 6.3 and 6.1(two doublets, 2H, aromatic); 4.0 (broad doublet, 1H); 1.3 (d, 3H,methyl); 1.1 and 0.7 (two singlets, 6H, gem-dimethyl).

Mass spectrum: m/e=406

EXAMPLE 5Trans-6a,10a-1-hydroxy-3-(5'-phenyl-2'-pentyloxy)-6,6-dimethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthren-9-P-ol

Under a nitrogen atmosphere, 12 mg of sodium borohydride was carefullyadded to a cold solution of thetrans-6a-10a-1-hydroxy-3-(5'-phenyl-2'-pentyloxy)-6,6-dimethyl-5,6,6a,7,8,9,10,10a-octahydrophenanthren-9-one in 4 ml of absolute ethanol and stirredfor 1.5 hours before the mixture was poured into 40 ml of cold 5%hydrochloric acid and extracted with ether (4×40 ml). The combined etherlayers were washed once with 50 ml of saturated sodium bicarbonate,dried (brine, magnesium sulfate), filtered, and concentrated to a clearcolorless oil which was chromatographed on 25 g of silica gel elutedwith 1:1 ether/hexane followed by ether. Combination and concentrationof the desired fractions gave 38 mg (56.5%) of the puretrans-9-β-hydroxy product as an oil.

NMR: 100 MHz; CDCl₃ δ: 7.3-7.0 (m, 5H, phenyl); 6.0 (doublet ofdoublets; 2H, aromatic); 0.9 and 0.6 (two singlets, 6H, gem-dimethyls);2.8-1.0 (m, remaining protons).

High-resolution mass spectrum calc m/e: C₂₇ H₃₆ O₃ ; 408.2676; found m/e408.2688.

EXAMPLE 62-Hydroxymethylene-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone

A solution of 2.2 g (5.3 mmoles) of6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone in 25 ml of ethylformate was added dropwise to 0.64 g (26.5 mmoles) of 50% sodium hydride(washed with pentane) and after dilution with 30 ml of ether was stirredovernight at room temperature. The reaction mixture was poured into anice cold mixture of 1 N hydrochloric acid and ether, the ether layer wasseparated, and the aqueous was extracted once with ether. The combinedether layers were washed twice with water, dried (brine, magnesiumsulfate), and concentrated to give a yellow oil which waschromatographed on 120 g of silica gel eluted with 4:1hexane/ethylacetate. Combination and concentration of the appropriatefractions gave 1.69 g; (72%) of the desired compound as an oil.

NMR: CDCl₃ ; δ: 1.3 (d, 3H, side chain methyl); 1.7 & 2.6 (M, 10H,methylene); 4.4 (broad singlet, 1H, methine); 5.2 (S, 2H, benzylic); 6.3(M, 2H, aromatic); 7.2 (S and 8.1-7.2(M), 12H, hydroxyl, vinyl andaromatic).

High resolution mass spectrum: calc. m/e 443.2222; found m/e 443.2218.

EXAMPLE 72-(3'-oxobutyl)-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone

A 1.69 g portion (3.8 mmoles) of2-hydroxymethylene-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralonesuspended in 10 ml methanol was stirred with 0.46 ml of methyl vinylketone and 0.13 ml triethylamine for 24 hours at room temperature. Thereaction mixture was mixed with ether, washed four times with an aqueoussolution of 10% sodium carbonate, and after drying (brine, magnesiumsulfate), the ether layer was concentrated to give 1.81 g (98%) of thedesired compound as an oil.

High resolution mass spectrum: m/e 484

In an alternative synthetic route, the desired2-(3'-oxobutyl)-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone wasobtained by reaction of 6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralonewith ethyl acetate according to the procedure of Example 6 to give2-hydroxymethylene-6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralone in98% yield.

Reaction of the latter with methyl vinyl ketone as described aboveyielded 2-(3'-oxobutyl)-6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralonein 55% yield. The desired2-(3'-oxobutyl)-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone wasformed in 21% yield from reaction of the 8-hydroxy compound with sodiumhydride in dry dimethyl formamide followed by the addition of benzylbromide at 0° C.

2-hydroxymethylene-6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralone:NMR: CDCl₃ ; δ: 1.25 (d, 3H, side chain methyl); 1.8 (m, 6H, methylene);2.6 (m, 5H, methylene); 4.4 (m, 1H, methine); 6.2 (S, 2H, aromatic); 7.2(S, 6H, aromatic & vinyl); 12.2 (S, 1H, hydroxyl).

MS: m/e-352

2-(3'-oxobutyl)-6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralone: NMR:CDCl₃ ; δ: 1.3 (d, 3H, side chain methyl); 1.6-3.0 (m, 17H, methyleneand methyl); 4.4 (6.5, 1H, methine); 6.2 (S, 2H, aromatic); 7.2 (S, 6H,aromatic & vinyl); 12.8 (S, 1H, hydroxyl).

High resolution mass spectrum: calc. m/e-394.2144; found m/e-394.2132.

EXAMPLE 81-Benzyloxy-3-(5'-phenyl-2'-pentyloxy)-5,6,6a,7,8,9-hexahydrophenanthren-9-one

A 1.8 g (3.7 mmoles) portion of2-(3'-oxobutyl-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone wasreacted with 40 ml 2 N potassium hydroxide in 40 ml of methanol at 0° C.for 0.5 hours before the mix was heated to reflux, under nitrogenatmosphere, overnight. The reaction mixture was neutralized at roomtemperature with acetic acid, and taken up in a mixture of ether-water.The ether layer was separated and the aqueous layer was extracted twicemore with ether. The combined ether extracts were washed twice withsaturated sodium bicarbonate, dried (brine, magnesium sulfate), andconcentrated to an oil 1.7 g (90%) which was used without furtherpurification.

NMR: CDCl₃ ; δ: 1.2 (d, 3H, side chain methyl); 1.65, 2.0, 2.6, 4.0(broad multiplets, 14H, methylene); 4.4 (M, 1H, methine); 5.1 (S, 2H,benzylic); 6.2 (S, 2H, aromatic); 7.3 (M, 10H, aromatic).

High resolution mass spectrum: calc. m/e 466.2508; found m/e 466.2478.

EXAMPLE 9 1-hydroxy-3-(5'-phenyl-2'-pentyloxy)-5,6,6a,7,8,9,10,10a-octahydrophenanthren-9-one and octahydrophenanthren-9-ol

100 ml of ammonia was liquified in a flame-dried apparatus placed into adry ice/acetone bath. A piece of lithium wire was then dissolved in theammonia to produce a deep blue colored solution and 1.7 g (3.64 mmoles)of the1-benzyloxy-3-(5'-phenyl-2'-pentyloxy)-5,6,6a,7,8,9-hexahydrophenanthren-9-onedissolved in 25 ml of dry tetrahydrofuran was slowly added after whichthe mixture was stirred for 10 minutes at -80° before solid ammoniumchloride was carefully added until all the blue color disappeared. Theliquid ammonia was evaporated and 75 ml of water was added to theresidue which was then extracted with ether (4×50 ml). The etherextracts were combined, dried (brine, magnesium sulfate), filtered andconcentrated to give an oil which was chromatographed on 200 g of silicagel eluted with 3:1 cyclohexane/ethyl acetate. Combination andconcentration of similar fractions gave 69 mg (5%) of isomeric9-keto-compounds as well as 634 mg (46%) of isomeric 9-hydroxycompounds.

9-keto compounds:

R_(f) in 1:1 ethyl acetate/hexane: R_(f) : 0.614 (silica gel)

NMR: CDCl₃ ; δ: 1.35 (d, 3H, side chain methyl); 1.5-3.4 (broadadsorption 18H, methylenes); 3.8 (bS, 1H, hydroxyl); 4.4 (S, 1H,methine); 6.3 (d, 2H, aromatic); 7.3 (M, 5H, aromatic).

High resolution mass spectrum: calc. m/e 378.2195; found m/e 378.2181.

9-hydroxy compounds:

R_(f) in 1:1 ethyl acetate/hexane: 0.283 (silica gel)

NMR: CDCl₃ ; δ: 1.35 (d, 3H, side chain methyl); 1.5-3.4 (broadabsorption, 18H, methylenex); 3.6(m), 3.95 (bS) and 4.3 (M), 4H,methines and hydroxyls; 6.2 (d, 2H, aromatic); 7.3 (M, 5H, aromatic).

High resolution mass spectrum: calc. m/e 380.332; found: m/e 380.2336.

EXAMPLE 10

Other compounds of formulae I, II and III having other substituents forR₁, R₂, R₃, R₄, Z and W, as described above herein, may be prepared bythe methods of Examples 1 through 5 and Examples 6 through 9 fromappropriately substituted tetralones of formula IV.

The substituted tetralones of formula IV may be prepared by the methodsshown in Example 11 through 43.

EXAMPLE 11 3,5-Dimethoxybenzylchloride

Over a period of 20 minutes a solution of 150 g (1.26 moles) of thionylchloride in 0.65 l of ether was added to 100 g (0.59 moles) of3,5-dimethoxybenzyl alcohol and 6.6 ml of pyridine in 1.35 l of ether.After stirring for 3 hr the solution containing the product wasseparated from the residual dark oil, concentrated, and the crudeproduct was redissolved in 1 l of ether, washed with water (3×250 ml),dried (brine, magnesium sulfate), filtered, and reconcentrated to give adark oil which was vacuum distilled: b.p. 115°-118° C. at 0.4 mm Hg.Upon standing, fractions containing the desired compound solidified togive 95.3 g (86%) of white solid, m.p. 43°-45° C.

EXAMPLE 12 2-Cyano-3,3-dimethyl-3-(3',5'-dimethoxyphenyl)butyric acid

A tetrahydrofuran solution of 3,5-dimethoxybenzyl magnesium chloride(prepared from 2.05 g (84 mmoles) of powdered magnesium and 15.0 g (80.4mmoles) of 3,5-dimethoxybenzyl chloride in 300 ml of dry tetrahydrofuranwas added dropwise to a solution of 9.23 g (60.3 mmoles) of ethylisopropylidene cyanoacetate and 0.40 g of cuprous chloride in 25 ml oftetrahydrofuran while maintaining the reaction temperature below 10° C.After the addition was complete, the reaction mixture was warmed to roomtemperature, stirred overnight and then poured into 300 ml coldsaturated aqueous ammonium chloride. The solution was extracted 3 timeswith 400 ml of ether and the combined extracts were washed 2 times with400 ml of water, dried (brine, magnesium sulfate) and concentrated togive 19.4 g of an oil which was hydrolyzed by treatment with aqueousethanolic potassium hydroxide at room temperature for 15 minutes. Thereaction mixture was concentrated to remove the ethanol and theresulting residue was taken up in a mixture of 300 ml ethyl acetate and150 ml water. The ethyl acetate layer was separated and washed with 150ml of water followed by 100 ml of saturated sodium bicarbonate.Acidification of the combined aqueous solutions with 10% hydrochloridacid at 0° C. gave an oil which was separated by extracting 4 times with150 ml of ether. The ether extracts were combined, washed with 150 ml ofwater, dried (brine, magnesium sulfate), filtered, and concentrated toyield 11.1 g (50%) of the desired compound as an oil.

NMR: CDCl₃ ; δ: 1.1 (S, 3H), 1.2 (S, 3H), 2.7 (S, 2H), 3.4 (S, 1H), 3.7(S, 6H), 6.3 (S, 3H), 10.0 (S, 1H).

EXAMPLE 13 3,3-Dimethyl-6,8-dihyroxy-1-tetralone

The 2-cyano-3,3-dimethyl-3-(3'-5'-dimethoxyphenyl)butyric acid (11.1 g;40.1 mmoles) was treated with 170 ml of 48% aqueous hydrogen bromide and170 ml og glacial acetic acid at reflux overnight. After cooling to roomtemperature and concentrating, the reaction mixture was treated with 300ml of water and extracted with ethyl acetate (3×150 ml). The combinedextracts were dried (brine, magnesium sulfate) and concentrated to givea dark foam (7.92 g), which was dissolved in a minimum amount ofbenzene/ethyl acetate and chromatographed on 350 g of silica gel elutedwith benzene followed by 20% ethyl acetate/benzene. The fractionscontaining the desired compound were combined and concentrated to anoil, which crystallized after treatment with hexane, 4.04 g (49%); m.p.115°-116° C. Recrystallization from ethyl acetate/hexane gave thedesired product as light tan needles; m.p. 116°-117° C. (C₁₂ H₁₄ O₃):Calc.: C: 69.89%; H: 6.84%; Fd. C: 70.26%, H: 6.74%.

EXAMPLE 14 3,3-Dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralone

A 1.68 g (8.15 mmoles) portion of 3,3-dimethyl-6,8-dihydroxy-1-tetraloneand 2.25 g (16.3 mmoles) of potassium carbonate were suspended in 8 mlof dry dimethyl formamide and reacted with 2.17 g (8.97 mmoles) of5-phenyl-2-pentyl methanesulfonate under nitrogen at 80° C. for 3.5hours. After cooling to room temperature the reaction was poured into100 ml of ice water and extracted with ethyl acetate (2×75 ml),acidified with 10% hydrochloric acid and further extracted with ethylacetate (2×50 ml). The combined organic phases were washed with water(4×40 ml), dried (brine, magnesium sulfate), filtered, and concentratedto a dark oil which was chromatographed on 120 g of silica gel elutedwith benzene/hexane (1:1) followed by benzene. Combination andconcentration of the proper fractions afforded 2.72 g (96%) of thedesired compound as an oil.

NMR: CDCl₃ ; δ: 1.0 (S, 6H gemdimethyl), 1.3 (D, 3H, J=7 Hz, side chainCH₃) 1.7 (M, 4H, ethylene), 2.5 (S, 2H, α-methylene), 2.7 (S, 2H, benzylmethylene), 2.7 (M, 2H, benzyl methylene), 4.1-4.6 (M, 1H, methine), 6.1(M, 2H, aromatic), 7.1-7.2 (M, 5H, aromatic), 13.0 (S, 1H, phenol).

EXAMPLE 153,3-Dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone

A solution of 1.36 g of3,3-dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralone in 7 ml ofdry dimethyl formamide was slowly added to 206 mg of pentane wshed 50%sodium hydride. After stirring for 1 hr at room temperature, the darkbrown mixture was chilled to 2° in an ice bath, treated dropwise with0.475 ml of benzyl bromide, stirred for 0.5 hrs at 0° C. then warmed toroom temperature and stirred for an additional 3 hours before beingpoured into a mixture of ice cold 1 N hydrochloric acid and ether. Theether layer was separated and the aqueous was extracted once more withether. The combined organic layers were washed with water, dried (brine,magnesium sulfate) and concentrated to a yellow oil which waschromatographed on 100 g of silica gel eluted with ether/hexane (1:1).Combination and concentration of the appropriate fractions gave 1.26 g(74%) of the desired compound.

NMR: CDCl₃ ; δ: 7.7-6.9 (M, 10H, phenyl aromatics), 6.3 and 6.2 (two-oneproton doublets, J=2 Hz, aromatic), 5.1 (S, 2H, benzyloxy methylene),4.7-4.2 (M, 1H, methine) 2.8 (S, 2H, benzylic methylene) 2.7 (T, 2H,benzylic methylene) 2.5 (S, 2H, benzylic methylene) 2.7 (T, 2H, benzylicmethylene) 2.5 (S, 2H, α-methylene(1.9-1.5 (M, 4H, ethylene) 1.3 (D, J=7Hz, 2H, methyl) 1.0 (S, 6H, gem-dimethyl).

EXAMPLE 16 6,8-Dimethoxy-1-tetralone

The tetralone was prepared according to the procedure of Huisgen, Seidl,and Wimmer; Ann., 677, 21 (1964), m.p. 58°-61° C., (lit. m.p. -62°-64°C.).

EXAMPLE 17 6,8-Dihydroxy-1-tetralone

The 6,8-dimethoxy-1-tetralone (3.0 g; 14.0 mmoles) was refluxedovernight with 20 ml of 48% aqueous hydrogen bromide and 20 ml ofglacial acetic acid. After cooling to room temperature, the reactionmixture was neutralized with a saturated sodium bicarbonate solution andextracted with ethyl acetate. The combined extracts were dried (brine,magnesium sulfate) and concentrated to afford a red solid which upontrituration with ether gave the desired comound as an off-white solid,1.77 g (71%); m.p. 209°-210° C.

NMR: CDCl₃ ; δ: 2.0 (M, 2H, methylene); 2.6 (M, 4H, methylene); 6.2 (S,2H aromatic), 9.2 (broad singlet, 1H, hydroxyl) and 12.65 (S, 1H,hydroxyl).

EXAMPLE 18 6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralone

A 1.77 g (9.9 mmoles) portion of 6,8-dihydroxy-1-tetralone and 2.7 g(19.8 mmoles) of potassium carbonate were suspended in 20 ml of drydimethyl formamide and reacted with 2.6 g (10.8 mmoles) of5-phenyl-2-pentyl methanesulfonate under nitrogen, at 80° C. for 3.5hours. After cooling to room temperature the reaction was poured into100 ml of ice water and extracted with ethyl acetate (2×75 ml),acidified with 10% hydrochloric acid and further extracted with ethylacetae (2×50 ml). The combined organic phases were washed with water(4×40 ml), dried (brine, magnesium sulfate), filtered and concentratedto a dark oil which was chromatographed on 130 g of silica gel elutedwith hexane/ether (1:1). Combination and concentration of the properfractions afforded 2.3 g; (72%) of the desired compound as an oil.

NMR: CDCl₃, δ: 1.4 (d, 3H, side chain methyl); 1.8 and 2.2 (broadabsorb.m, 12H, methylene); 4.4 (broad singlet, 1H, methine) 6.2 (S, 2Haromatic); 7.2 (S, 5H, aromatic); 12.65 (S, 1H, hydroxyl).

EXAMPLE 19 6-(5'-phenyl-2'-pentyloxy)-8-benzyloxy-1-tetralone

A solution of 2.3 g of 6-(5'-phenyl-2'-pentyloxy)-8-hydroxy-1-tetralonein 15 ml of dry dimethyl formamide was slowly added to 187 mg of 50%sodium hydride washed with pentane. After stirring for 1 hr at roomtemperature, the mixture was chilled to 2° in an ice bath, treateddropwise with 0.92 ml of benzyl bromide, stirred for 0.5 hours at 0° C.then warmed to room temperature and stirred overnight before beingpoured into a mixture of ice cold 1 N hydrochloric acid and ether. Theether layer was separated and the aqueous layer was extracted once morewith ether. The combined organic layers were washed with water, dried(brine, magnesium sulfate), and concentrated to an oil which waschromatographed on 120 g of silica gel eluted with hexane/ethyl acetate(3:1). Combination and concentration of the appropriate fractions gave2.21 g (77%) of the desired compound.

NMR: CDCl₃ ; δ: 1.25 (D, 3H, side chain methyl); 1.75 and 2.1 (M, 6H,methylene) 2.8 (M, 6H, methylene), 4.4 (broad singlet, 1H, methine); 5.2(S, 2H, benzylic); 6.3 (m, 2H, aromatic); 7.2 (S&M, 10H, aromatic).

EXAMPLE 20 3-Methoxyisophthalaldehydic acid methyl ester

To a -78° to -100° solution of 1.0 mol of 3-methoxyisophthalic aciddimethyl ester in 1-10 l of toluene is slowly added 1.0 mol ofdiisobutylaluminum hydride as a 1 M solution in n-hexane. The reactionis stirred for 3 hours after the addition and then quenched by theaddition of 10 mol of anhydrous methanol. The reaction is allowed towarm to room temperature and stirred until a filterable precipitateforms. The reaction is filtered and the filtrate evaporated to aresidue. The residue is purified by crystallization, distillation orchromatography to yield 3-methoxyisophthalaldehydic acid methyl ester.

EXAMPLE 21 3-chloromethyl-5-methoxybenzaldehyde ethylene glycol acetal

A 0.1 mol portion of 3-methoxyisophthalaldehydic acid methyl ester isheated overnight in 200-300 ml of ethylene glycol containing a catalyticamount of p-toluene sulfonic acid. The reaction is cooled, diluted withdilute aqueous sodium bicarbonate and extracted with ether. After dryingwith anhydrous sodium sulfate the ether exacts are concentrated to yielda mixture of methyl and β-hydroxy ethyl esters of the acetal. Thismixture is dissolved in ether or tetrahydrofuran and added to an excess(0.1 mol) of lithium aluminum hydride in ether. After the reduction iscomplete the mixture is worked-up by addition of water and 6 N sodiumhydroxide to precipitate the inorganic salts. The ether is dried andevaporated to give the crude benzyl alcohol-acetal. This benzylalcohol-acetal is heated with 150 ml of thionyl chloride in ether with acatalytic amount of pyridine. After evolution of gases is complete theexcess thionyl chloride is removed under vacuum. The benzyl chloride isthen purified by column chromatography or vacuum distillation.

EXAMPLE 22 3-butyl-6-formyl-8-hydroxy-1-tetralone

The Grignard reagent of 3-chloromethyl-5-methoxybenzaldehyde ethyleneglycol acetal is formed and added to ethyl 2-cyano-2-heptenoate (R.Carrie, R. Bougot and B. Potteau, Compt. Rend. 259, 2859 (1964)) usingprocedures described in Example 12. The adduct thus obtained is cyclizedto the tetralone, the methoxy ether cleared and the acetal hydrolyzedusing the hydrogen bromide procedure described in Example 13.

EXAMPLE 23 3-butyl-6-formyl-8-benzyloxy-1-tetralone

The product of Example 22 is treated with sodium hydride and benzylbromide according to the procedures described in Example 15.

EXAMPLE 24 3-butyl-6-[6'-(2'-pyridyl)benzyl]-8-hydroxy-1-tetralone

A mixture of 0.015 mol of 2-(5'-bromopentyl)pyridine (J. Krapcho and W.A. Lott, U.S. Pat. No. 2,918,470) and 0.015 mol of triphenylphosphine in15 ml of xylene is refluxed for 18 hours, cooled to room temperature,filtered and the resulting triphenylphosphonium bromide is washed withether and dried. Under a nitrogen atmosphere a mixture of 0.011 mol ofthis triphenylphosphonium bromide in 15 ml of dimethylsulfoxide and0.011 mol of 3-butyl-6-formyl-8-benzyloxy-1-tetralone in 10 ml oftetrahydrofuran is added dropwise to a slurry of 0.57 g of 50% sodiumhydride in 5 ml of tetrahydrofuran while maintaining the temperature at0°-5°. After the addition is completed the reaction is stirred foranother hour at 0°-5°, concentrated under vacuum, diluted with about 60ml of water and acidified with 6 N hydrochloric acid. The aqueoussolution is extracted with benzene to remove the triphenylphosphineoxide and the aqueous layer is made basic and extracted withethylacetate. Evaporation of the ethylacetate gives the intermediatealkene as an oil. A mixture of this oil, 25 ml of absolute methanol,0.15 ml of concentrated hydrochloric acid and 0.3 g of 10% palladium oncarbon is hydrogenated in a Parr shaker for one day at 55 psi hydrogen.The mixture is filtered through celite and concentrated under vacuum.Addition of ether yields the desired product as the hydrochloride salt,which is filtered off, washed with ether and dried.

The free base is obtained by dissolving the hydrochloride salt inaqueous ethanol adding aqueous sodium bicarbonate, extracting withethylacetate, drying and removing the solvent under vacuum.

EXAMPLE 25 Methyl 3-acetyl-5-methoxybenzoate

A solution of 0.5 mol of dimethyl 3-methoxy-isophthalate is dissolved inaqueous methanol containing an equivalent amount (0.5 mol) of potassiumhydroxide. The reaction is warmed to about 50° C. and stirred until thehydrolysis is complete. Acidification with 6 N hydrochloric acid,extraction with ether, and evaporation of the ether yields thehalf-ester which is added to 300 ml of thionyl chloride and heated untilevolution of sulfur dioxide and hydrogen chloride ceases. The excessthionyl chloride is removed under vacuum and the half-ester-acidchloride is purified by vacuum distillation. A 0.2 mol portion of thiscompound in 75 ml of ether is added over a 15 minute period to 0.22 molsof a solution of ethoxymagnesiummalonic ester (prepared by the method ofReynolds and Hauser, Org. Syn. Col. Vol. IV, 708 (1963)) while heatingat reflux. The mixture is cooled, shaken with dilute sulfuric acid todissolve the solids, the ether phase separated, the aqueous layerextracted with ether and the combined ether layers washed with water andconcentrated. The resulting material is added to a solution of 60 ml ofglacial acetic acid, 7.6 ml of concentrated sulfuric acid and 40 ml ofwater and heated under reflux for 4 hours or until no more carbondioxide is evolved. The reaction mixture is concentrated and taken up inether, dried and the ether evaporated to give 3-acetyl-5-methoxybenzoicacid. Reaction of this acid with thionyl chloride, followed by additionof methanol to the acid chloride yields methyl3-acetyl-5-methoxybenzoate which is purified by vacuum distillation.

EXAMPLE 26 3-chloromethyl-5-methoxyacetophenone ethylene glycol ketal

Methyl 3-acetyl-5-methoxybenzoate is reacted with ethylene glycolfollowed by reduction with lithium aluminumhydride and converted to thebenzyl chloride using the procedures described in Example 21.

EXAMPLE 27 3-methyl-3-ethyl-6-acetyl-8-hydroxy-1-tetralone

The Grignard reagent of 3-chloromethyl-5-methoxyacetophenone ethyleneglycol acetal is formed and added to ethyl 2-cyano-3-methyl-2-pentenoate(F. S. Prout et. al., Org. Syn. Col. Vol. IV, 93 (1963)) using theprocedures described in Example 12. The adduct obtained is cyclized tothe tetralone, the methoxy ether cleaved and the ketal hydrolized usingthe procedure described in Example 13.

EXAMPLE 28 3-methyl-3-ethyl-6-acetyl-8-benzyloxy-1-tetralone

The product of Example 27 is treated with sodium hydride and benzylbromide according to the procedures in Example 15.

EXAMPLE 293-methyl-3-ethyl-6-[6'-(N-methyl-2'-piperidyl)-2'-pentyl-8-hydroxy-1-tetralone

N-methyl-2-(3'-bromopropyl)-piperidine (W. L. Meyer and N. Sapionchioy,J. Am. Chem. Soc. 86, 3343 (1964)) is converted to thetriphenylphosphorone, reacted with the product of Example 28 andcatalytically reduced to the desired compound according to theprocedures described in Example 24.

EXAMPLE 30 3-ethyl-6-formyl-8-hydroxy-1-tetralone

The Grignard reagent of 3-chloromethyl-5-methoxy-benzaldehyde ethyleneglycol acetal produced as in Example 21 is formed and added to ethyl2-cyano-2-pentenoate (F. D. Popp and A. Catals, J. Org. Chem., 26, 2738(1961)) using procedures described in Example 12. The addition productobtained is cyclized to the tetralone, the methoxy ether cleaved and theacetal hydrolyzed using the aqueous hydrogen bromide procedure describedin Example 13.

EXAMPLE 31 3-ethyl-6-formyl-8-benzyloxy-1-tetralone

The product of Example 30 is treated with sodium hydride and benzylbromide according to the procedure described in Example 15.

EXAMPLE 32 4-cyclohexylbutyloxy chloromethyl ether

4-cyclohexylbutyric acid (Aldrich) is reduced with excess lithiumaluminum hydride in ether to yield 4-cyclohexyl-1-butanol (D. S. Hiersand R. Adams, J. Am. Chem. Soc., 48 2385 (1926)) which ischloro-methylated with hydrogen chloride and formaldehyde to yield thedesired compound.

EXAMPLE 33 3-ethyl-6-cyclohexylbutoxyethyl-8-hydroxy-1-tetralone

4-cyclohexylbutoxymethyl chloride is formed by the method of Example 32,converted to the triphenylphosphorone, reacted with the product ofExample 31 and is then reduced catalytically to the desired compoundusing procedures analogous to those described in Example 24.

EXAMPLE 34 Ethyl 2-cyano-3-benzyl-2-pentenoate

1-phenyl-2-butanol (0.12 mol) is condensed with ethyl cyanoacetate (0.10mol) using the procedure of Prout et al (Org. Synth. Coll. Vol. IV, 93,(1963)).

EXAMPLE 35 3-ethyl-3-benzyl-6-formyl-8-hydroxy-1-tetralone

The Grignard reagent of 3-chloromethyl-5-methoxybenzaldehyde ethyleneglycol acetal of Example 21 is formed and added to ethyl2-cyano-3-benzyl-2-pentenoate using the procedures described in Example12. The adduct obtained is cyclized to the tetralone, the methyl ethercleaved, and the acetal hydrolyzed using the aqueous hydrogen bromideprocedure of Example 13.

EXAMPLE 36 3-ethyl-3-benzyl-6-formyl-8-benzyloxy-1-tetralone

The product of Example 35 is benzylated with benzyl bromide as describedin Example 15.

EXAMPLE 37 3-ethyl-3-benzyl-6-carbethoxyethyl-8-hydroxy-1-tetralone

Ethyl bromoacetate is converted to the triphenyl phosphorone, reactedwith the product of Example 36 and reduced catalytically to the desiredcompound using procedures analogous to those described in Example 24.

EXAMPLE 38 3-ethyl-4-benzyl-6-(3'-hydroxypropyl)-8-hydroxy-1-tetraloneethylene glycol ketal

A 0.05 mol portion of the product of Example 37 is added to 50 ml ofethylene glycol containing 0.1 g of p-toluene sulfonic acid. Afterheating for 2-3 days the reaction is cooled, neutralized with aqueoussodium bicarbonate and extracted with ether. The ether layer is driedand concentrated. The redisual ketal is added directly to 0.05 mol oflithium aluminumhydride in ether and refluxed. After the reduction iscomplete the mixture is worked up by the addition of water and 6 Nsodium hydroxide to precipitate the inorganic salts. The ether is driedand evaporated to give the crude alcohol-ketal.

EXAMPLE 39 3-ethyl-3-benzyl-6-(3'-mesyloxypropyl)-8-mesyloxy-1-tetraloneethylene glycol ketal

0.03 mol of the product of Example 38 is dissolved in tetrahydrofurancontaining 0.12 mol of triethyl amine and cooled to 0°-5°. Methanesulfonyl chloride (0.07 mol) is added dropwise, the reaction allowed tocome to room temperature and stirred for another hour. The triethylaminehydrochloride is removed by filtration and the tetrahydrofuranconcentrated and the residue is dissolved in chloroform, washed withwater, dried and concentrated to the desired product which is usedwithout further purification.

EXAMPLE 40 3-ethyl-3-benzyl-6-(3'-ethylthiopropyl)-8-hydroxy-1-tetralone

Under a nitrogen atmosphere 0.02 mol of the product of Example 39 wasdissolved in 25 ml of dimethyl formamide and 0.04 mol of sodium ethylmercaptide is added and the mixture stirred at room temperatureovernight. The mixture is then heated to 70° for 3 hours, cooled, pouredinto water, then acidified with aqueous hydrochloric acid and stirredfor several hours. Extraction with ethylacetate, drying the extracts andevaporation of the solvent give the crude product which is purified bychromatography.

EXAMPLE 41 3,3-dimethyl-6-(2'-pyridylmethyloxy)-8-hydroxy-1-tetralone

A 1.68 g (8.2 mmol) portion of 3,3-dimethyl-6,8-dihydroxy-1-tetraloneprepared as in Example 13 and 2.25 g (16.3 mmol) of potassium carbonateis suspended in 8 ml of dry dimethyl formamide and reacted with 1.25 g(9 mmol) of 2-picolyl chloride under nitrogen at 50°-80° for 4-5 hours.After cooling the reaction mixture is poured into 100 ml of ice-wateracidified with hydrochloric acid, made basic with sodium bicarbonate andextracted with chloroform and ethylacetate. The combined organic phasesare washed with water, dried (brine and sodium sulfate), filtered andconcentrated to an oil is chromatographed to yield the desired product.

EXAMPLE 42 Methyl 3-(1',2'-dimethylheptyl)-5-methoxybenzoate

A mixture of 0.03 mol of 2-bromoheptane and 0.03 mol oftriphenylphosphine in 30 ml of xylene is refluxed for 18-24 hours,cooled to room temperature and the resulting triphenyl phosphoniumbromide is filtered, washed with ether and dried. A mixture of thismaterial (0.022 mol) dissolved in 30-50 ml of dimethyl sulfoxide under anitrogen atmosphere and 0.022 mol of methyl 3-acetyl-5-methoxybenzoateformed as in Example 25 in 10 ml of tetrahydrofuran is added dropwise toa slurry of 1.2 g of 50% sodium hydride in 10 ml of tetrahydrofuranwhile maintaining the temperature at 0°-5°. After the addition iscompleted the reaction is stirred overnight at room temperature,concentrated under vacuum, diluted with 100-150 ml of water and theproduct extracted with pentane-ether. The extracts are combined, washedwith water, dried and the solvents removed under vacuum. The alkene thusobtained is purified by chromatography on silica gel.

This alkene is dissolved in 50 ml of absolute methanol and 0.3 ml ofconcentrated hydrochloric acid and hydrogenated for one day at 55 psi ofhydrogen on a Parr shaker containing 0.3 g of palladium on carbon. Thereaction mixture is then filtered through celite and concentrated undervacuum and chromatographed or vacuum distilled to obtain the desiredproduct.

EXAMPLE 43 3-(1',2'-dimethylheptyl)-5-methoxybenzyl chloride

A 0.01 mol portion of methyl 3-(1',2'-dimethylheptyl)-5-methoxybenzoateis dissolved in tetrahydrofuran and added to 0.01 mole of lithiumaluminum hydride in tetrahydrofuran. After the reduction is complete themixture is worked-up by addition of water and 6 N sodium hydroxide toprecipitate the inorganic salts. The tetrahydrofuran is dried andevaporated to give the crude benzyl alcohol. This benzyl alcohol isheated with thionyl chloride following the procedures in Example 11.

What is claimed is:
 1. A compound of the formula ##STR9## wherein R'₁ isselected from hydrogen, alkanoyl of 1 to 6 carbon atoms and benzoyl;R₃is selected from hydrogen, methyl and ethyl; R₄ is selected fromhydrogen, alkyl of 1 to 6 carbon atoms and benzoyl; Z is selected from:(a) alkylene having from one to nine carbon atoms; (b)-(alk₁)_(m)-X-(alk₂)_(n) - wherein each of (alk₁) and (alk₂) is alkylene havingfrom 1 to 9 carbon atoms, with the proviso that the summation of carbonatoms in (alk₁) plus (alk₂) is not greater than 9; m and n are each 0 or1; X is selected from O, S, SO and SO₂ ; and W is selected from pyridyland piperidyl.
 2. A compound according to claim 1 wherein R₃ and R₄ areeach hydrogen or methyl.
 3. A compound according to claim 2 wherein Z isalkylene of 4 to 9 carbon atoms.
 4. A compound according to claim 3wherein Z is --CH(CH₃)--(CH₂)₃ --.
 5. A compound according to claim 3wherein Z is --CH(CH₃)--CH(CH₃)--(CH₂)₄ --.
 6. A compound according toclaim 2 wherein Z is -(alk₁)_(m) -X-(alk₂)_(n) -.
 7. A compoundaccording to claim 6 wherein Z is -(alk₁)_(m) -O-(alk₂)_(n) -.
 8. Acompound according to claim 7 wherein Z is -O-(alk₂), wherein (alk₂) hasfrom 4 to 9 carbon atoms.
 9. A compound according to claim 8 wherein Zis --O--CH(CH₃)--(CH₂)₃ --.